ici-154129 and ubenimex

In the present study we report the effects of inhibitors of enkephalin-degrading peptidases on spontaneous locomotion in mice and the involvement of delta opioid receptors in these effects. Animals received intracerebroventricularly (i.c.v.) or intravenously (i.v.) enkephalinase inhibitors (thiorphan and acetorphan), aminopeptidase inhibitors (bestatin and carbaphethiol) or mixed peptidase inhibitors (kelatorphan). The i.c.v. co-administration of bestatin and thiorphan (50 micrograms + 50 micrograms) induced an increase in both the horizontal and vertical components of locomotion. A similar pattern was observed after the i.c.v. administration of kelatorphan (8.5-50 micrograms) or the i.v. co-administration of acetorphan and carbaphethiol (5 mg/kg + 10 mg/kg). The opiate antagonist naltrexone (1 mg/kg, s.c.) failed to reverse the excitolocomotor effects of kelatorphan or of bestatin and thiorphan and antagonized only partially the effects of acetorphan and carbaphethiol. Naloxone (2 mg/kg-10 mg/kg, s.c.) partially reversed the increase in locomotion elicited by bestatin and thiorphan. The pretreatment with the delta opioid antagonists ICI 154,129 (20 micrograms, i.c.v.) or ICI 174,864 (2-4 micrograms, i.c.v.) strongly decreased the effects of all the peptidase inhibitors we tested. These results suggest that endogenous enkephalins may control via delta opioid receptors the horizontal and vertical components of locomotor activity in mice.

Topics: Aminopeptidases; Animals; CD13 Antigens; Dipeptides; Drug Synergism; Enkephalin, Leucine; Enkephalins; Injections, Intravenous; Injections, Intraventricular; Leucine; Locomotion; Male; Mice; Naloxone; Neprilysin; Phenylcarbamates; Prodrugs; Receptors, Opioid; Receptors, Opioid, delta; Sulfhydryl Compounds; Thiorphan

The analgesic activity of some opioid peptides which display a relative selectivity for either the mu-receptor subtype, [D-Ala2, MePhe4, Gly-ol5]enkephalin (DAGO) or the delta-receptor subtype. [D-Ala2, D-Leu5]enkephalin (DADLE), [D-Ser2, Leu5]enkephalyl-Thr (DSLET) and [D-Thr2, Leu5]enkephalyl-Thr (DTLET) is highly correlated with their affinity for central or peripheral mu- but not delta-receptors. Moreover their analgesic effects as well as those elicited by degrading enzyme inhibitors (bestatin + thiorphan) of endogenous enkephalins were easily antagonized by naloxone with similar pA2 values but not by the delta-antagonist ICI 154,129. Therefore the analgesia produced by opioid peptides including endogenous enkephalins is likely connected to mu-receptor stimulation. Finally, there was no obvious potentiation by delta-agonists of the analgesia resulting from either administration of the mu-agonist morphine or endogenous enkephalins. This suggested that in the hot plate test, there is no modulation of the effect resulting from mu-receptor stimulation by a delta-receptor interaction. Likewise, enkephalinergic activity such as that due to thiorphan + bestatin does not appear to be regulated through mu- or delta-receptor stimulation.

Topics: Analgesics; Animals; Enkephalin, Leucine; Enkephalins; Guinea Pigs; In Vitro Techniques; Leucine; Male; Mice; Morphine; Muscle Contraction; Muscle, Smooth; Nalorphine; Naloxone; Receptors, Opioid; Receptors, Opioid, delta; Receptors, Opioid, mu; Thiorphan; Tiopronin